[unreadable] The use of non-viral gene delivery vectors (plasmid based vectors) is attractive because these vectors avoid potential problems associated with the use of viruses. Unfortunately, they remain less effective than viruses in most current models, in order to increase their efficiency, one approach is to mimic microbial infection pathways and incorporate these features into a plasmid delivery system. Several recent studies suggest that this can increase the utility of non-viral based systems based on an increased understanding of the viral mechanisms of cell attachment and entry intracellular transport. In this proposal, we will continue this approach in detail using two microbes as examples AAV is one of the simplest viruses proven to be effective for in vivo transfections. Our investigations will follow two distinct aims that are based on the mechanisms that microorganisms employ to deliver its nucleic acids. Aim 1 will involve methods to increase nuclear accumulation of plasmid DNA while Aim2 will use a novel method to increase intracellular plasmid distribution These novel hypotheses will be investigated using a high risk approach that involves non-viral vectors; if supported by our results, they may lead to a new type of vector for researchers in the gene therapy arena that could have large-scale consequences for health care. [unreadable] [unreadable] [unreadable] [unreadable]